Nontuberculous mycobacteria (NTM) are increasingly recognized as important pulmonary pathogens in cystic fibrosis (CF). Individuals with CF have markedly increased risk of pulmonary NTM infection, with an estimated 200-fold greater prevalence than the general population. Nearly 40% of infected individuals develop debilitating disease with significant loss of lung function. The epidemiology and host-specific risk factors for NTM in CF are poorly understood. Diagnosis of NTM is often delayed, contributing to poor outcomes. One condition that deserves further attention as a risk factor for NTM in CF is vitamin D deficiency (VDD), which is very common in CF due to pancreatic exocrine insufficiency. Vitamin D plays an instrumental role in host control of Mycobacterium tuberculosis (TB), a close relative of NTM. VDD increases risk for TB infection and progression from latent to active TB disease. In CF, whether or not VDD increases risk of NTM infection or disease in CF is unknown. Identifying seasonal trends of infectious diseases improves the understanding of risk factors and enhances diagnostic screening practices. Seasonal variation of TB is well described, with incident infection increasing in the spring. VDD, resulting from limited sunlight exposure during winter, is thought to significantly contribute to this pattern. It is unknown, however, whether there is seasonal variation of NTM in CF. We hypothesize that VDD increases the risk for pulmonary NTM infection and progression to active NTM disease in CF. To investigate this hypothesis, we will perform two studies. One is a multi-center retrospective study exploring historical data from over 1,000 individuals with CF to evaluate the association between VDD and NTM infection and disease. The second investigation is a prospective observational study, nested in the framework of two larger, on-going Cystic Fibrosis Foundation funded studies named PREDICT and PATIENCE, which collectively seek to standardize the approach to the diagnosis and treatment of NTM in CF. In our proposed study, we will monitor participants with NTM positive respiratory cultures for progression to NTM disease and analyze the association of progression to disease with baseline vitamin D levels. We additionally hypothesize that seasonal variation exists in incident NTM infection within CF. We will test this hypothesis via an analysis of seasonal rates of incident NTM positivity utilizing the national Cystic Fibrosis Foundation Patient Registry. This proposal aims to elucidate the role of a potentially modifiable risk factor in the development and progression of NTM lung disease in CF, and understand the seasonal variation of incident NTM infection in CF. In doing so, these studies have the potential to inform future investigations of risk modification, therapeutically targeting vitamin D deficiency, as well as optimizing NTM screening practices in CF which could improve the diagnosis of a clinically significant pathogen in this uniquely at-risk population.